Despite considerable advances in the treatment of cardiovascular disease, it remains the leading cause of death in developed countries. Assessment of classic cardiovascular risk factors—including high blood pressure, diabetes and smoking—has a central role in disease prevention. However, many individuals with coronary heart disease (a narrowing of the blood vessels that supply the heart) have only one, or none, of the classic risk factors. Thus, new biomarkers are needed to augment the information obtained from traditional indicators and to illuminate disease mechanisms.
The search for reliable biomarkers of future MACE risk assessment seems to be significant task of modern in vitro diagnostics. MACE comprises acute coronary syndrome (ACS), unstable angina pectoris, myocardial infarction (MI) comprising ST-elevation MI and non-ST-elevated MI and some other events. In spite of wide group of candidates to be used for MACE risk assessment, described in literature, none of them became a gold standard biomarker such as cardiac Troponin I (cTnI) for myocardial infarction or NT-proBNP for heart failure diagnosis. The major disadvantages of the biomarkers of MACE risk assessment used in the clinical practice are insufficient cardiovascular specificity, unobvious relationship between the blood levels of analyte and oncoming cardiovascular complications, and as a result—limited prognostic value. There is an urgent need for biomarkers that could be used in emergency department for the MACE risk assessment of patients with acute chest pain without clear signs of acute myocardial infarction (having negative Troponin tests and no ST-elevation on an electrocardiogram). Such biomarker could also open up a possibility to screen the group of patients having classic cardiovascular risk factors to identify the subgroup of higher risk of short-term cardiac events.
Studies of inflammatory biomarkers related to atherosclerotic plaques destabilization has opened up a new prospective in the risk assessment of MACE. Wide family of candidate biomarkers (high-sensitivity C-reactive protein (hsCRP), Lipoprotein-associated Phospholipase A2 (Lp-PLA2), Matrix Metalloproteinase-9, Monocyte Chemotactic Protein-1, Soluble CD40L, Myeloperoxidase, etc.) has been intensively investigated during the last decade. Sufficient published evidence has been accumulated to support the utility of two of them—hsCRP and Lp-PLA2 in clinical practice.
In the present invention the fragments of IGFBP-4 and IGFBP-5 are proposed as biomarkers for MACE prediction. Specific proteolysis is a major regulatory mechanism of IGFBP-4 and IGFBP-5 function. Pregnancy-associated plasma protein-A (PAPP-A) was described in literature as an enzyme, responsible for the IGFBP-4 and IGFBP-5 proteolysis and subsequent release of active IGFs. Despite of proteolytic activity of PAPP-A inside of atherosclerotic plaque was not proved, it was speculated that in atherosclerotic plaques PAPP-A expressed by activated smooth muscle cells enhances IGF's bioavailability. We suggest using proteolytic fragments of IGFBP-4 and IGFBP-5 as independent blood biomarkers that could be used for the prediction of MACE.